Bismuth triflate-catalyzed oxa- and thia-Pictet-Spengler reactions: access to iso- and isothio-chroman compounds

Article abstract of DOI:10.1016/j.tetlet.2008.07.007

A new route to functionalized iso(thio)chromans is described. The compounds are accessible easily in a one pot-reaction by using different benzaldehydes and phenylethanethiol or phenylethanol in presence of bismuth triflate.

Full text of DOI:10.1016/j.tetlet.2008.07.007

Tetrahedron Letters 49 (2008) 5449–5451
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Tetrahedron Letters
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Bismuth triflate-catalyzed oxa- and thia-Pictet–Spengler reactions:
access to iso- and isothio-chroman compounds
*
Christian Lherbet , David Soupaya, Cécile Baudoin-Dehoux, Chantal André,
Casimir Blonski, Pascal Hoffmann
Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intêret Biologique, UMR CNRS 5068, Université Paul Sabatier Groupe de Chimie Organique Biologique 118,
Route de Narbonne, 31062 Toulouse Cedex 9, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A new route to functionalized iso(thio)chromans is described. The compounds are accessible easily in a
one pot-reaction by using different benzaldehydes and phenylethanethiol or phenylethanol in presence
of bismuth triflate.
Received 14 May 2008
Revised 26 June 2008
Accepted 1 July 2008
Available online 4 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Thia-Pictet–Spengler
Iso(thio)chroman
Aldehydes
Bismuth triflate
Phenylethanethiol
Many isochroman derivatives are of interest in several pharma-
ceutical areas, since they exhibit a variety of biological proper-
ties.1,2 The isochromanic structure is obtained by a variety of
synthetic methods, the oxa-Pictet–Spengler reaction, in which a
b-arylethylalcohol undergoes ringclosure after condensation with
an aldehyde, being one of the most convenient methods. Other-
wise, the isothiochroman ring structure (1H-2-benzothiopyran)
has proven to be a convenient precursor for the synthesis of iso-
quinolin, tetrahydronaphthalene or isochroman analogues3,4 and
to also exhibit pharmacological properties as glucose-6-phosphate
inhibitors or estrogen receptor binding molecules. To access to
isothiochroman compounds, a number of synthetic approaches
have been developed including intramolecular cyclization of phen-
ylethanethiol in the presence of catalytic amounts of Lewis acids,5
intramolecular cyclization from thioacetal6 or from phenylmetha-
nethiol derivatives7 or from enediynes under acidic conditions.8
There are few reports describing the preparation of 1-arylated
isothiochromans (1-aryl-3,4-dihydro-1H-benzothio-pyrans), for
example, by reaction of 1-brominated isothiochroman compounds
with aryl magnesium bromide.9
(unpublished results). Therefore, we envisaged to investigate
whether other acid catalysts would improve our procedure for
the preparation of the isothiochroman ring system through a
‘Pictet–Spengler’ like reaction (called thia-Pictet–Spengler), and
considered the use of bismuth(III) salts for their preparation.
Bismuth(III) salts as Lewis acids have been proved to efficiently
catalyze a number of reactions like Michael reactions,10 acylation
reactions,11 oxidation of
a
-ketols12 or epoxides13 and Diels–Alder
reactions.14 Additionally, Bi(III) salts have been found to catalyze
Mannich reactions, the intermolecular variant of a Pictet–Spengler
process.15
Moreover, compared to other Lewis acids such as AlCl3, ZnCl2 or
SnCl4, bismuth salts have been shown to be less toxic, and to be
generally more stable in solution, particularly in protic solvents
like water or methanol.
In this study, we report an efficient one-pot racemic synthesis of
isothiochromans, or isochromans, by using Bi(OTf)3 as Lewis acid
catalyst (Table 1), and show that Bi(OTf)3 catalyzes both formation
of the dithioacetal intermediate and the subsequent intramole-
cular cyclization leading to the isothiochroman compounds.
In the presence of 0.1 equiv of bismuth triflate, phenylethaneth-
iol reacted at room temperature with 3-nitrobenzaldehyde to yield
almost quantitatively the corresponding dithioacetal, and only
trace of the cyclized compound was observed, as evidenced by
1H NMR (Table 1). A similar reaction was reported for the protec-
tion of aldehydes with ethanedithiol in the presence of catalytic
amount of bismuth nitrate.16 The S,S-acetalization of aldehydes
As part of a project that aims to discover novel inhibitors of
coenzyme A-dependant enzymes, we prepared with moderate
yields, a series of isothiochroman compounds by mixing aryletha-
nethiol with formaldehyde in the presence of hydrogen bromide
* Corresponding author. Tel.: +33 561 55 68 07; fax: +33 561 85 60 11.
E-mail address: lherbet@chimie.ups-tlse.fr (C. Lherbet).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.007

5450
C. Lherbet et al. / Tetrahedron Letters 49 (2008) 5449–5451
Table 1
Synthesis of isothiochroman (or isochroman) in a one-pot reaction
O
O2N
XH
H
+
X
X
X
catalyst
toluene
X = O, S
NO2
NO2
A
B
conditions (X = S)
See Entries 5 and 6
Entry
X
Catalyst
Conditions
Yieldsa A/B, (%)
1
2
3
4
5
6
S
S
S
O
S
S
Bi(OTf)3 (0.1 equiv)
Bi(OTf)3 (0.1 equiv)
Bi(OTf)3 (0.02 equiv)
Bi(OTf)3 (0.1 equiv)
—
rt
Traces/96
88/no
100 °C, 2 h
100 °C, 2 h
110 °C, 6 h
100 °C, 2 h
100 °C, 2 h
75/25b
80/0
Traces/95
91/no
Bi(OTf)3 (0.1 equiv)
a
Yields after purification by flash chromatography.
Ratio observed by 1H NMR of crude reaction mixture.
b
or ketones was also described by using BiX3 (X = Cl, Br and I).17 We
examined a variety of reaction conditions to obtain isothiochro-
mans and found that the process was usually most efficient in
toluene at 100 °C. Using these conditions, the product was
obtained in yields approaching 90% after routine purification by
flash chromatography.18
In order to investigate the mechanism, the reaction was per-
formed starting from the isolated thioacetal intermediate. In that
case, no reaction was observed in the absence of Bi(III) (Table 1,
entry 5), but cyclization to the expected isothiochroman occurred
when the thioacetal was heated at 100 °C in the presence of the
bismuth catalyst (0.1 equiv) for 2 h (Table 1, entry 6). The effi-
ciency of bismuth to catalyze the reaction encouraged us to try
the same conditions with phenylethanol instead of phenyletha-
nethiol in order to see the impact of the heteroatom on the reaction
(Table 1, entry 4). Optimization of reaction conditions resulted in
yields up to 80% after heating at 110 °C for at least 6 h. As evi-
denced by 1H, 13C NMR and by TLC, the acetal product is the inter-
mediate in the reaction.
According to Guiso et al., a three-step reaction mechanism is
observed involving an acid-catalyzed hemiacetal formation fol-
lowed by dehydration to give the oxonium ion intermediate, and
further cyclization.19 In our case, the acetal is the result of the first
step followed by an alcohol or thiol loss, thus leading to the oxo-
nium or sulfonium ions. From our results, we conclude that Bi(III)
catalyzes both the dithioacetal formation and the cyclization reac-
tion leading to the isothiochroman, as proposed in Scheme 1.
Under optimal conditions, different isothiochroman or isochro-
man compounds were synthesized from phenylethanethiol or
phenylethanol and a series of benzaldehydes (Table 2). Good yields
in the range of 40–94% were obtained for all reactions, even with
sterically hindered aldehydes such as 2-methoxybenzaldehyde or
2,6-dichlorobenzaldehyde (Table 2, entries 2 and 11). An X-ray
structure was determined for the racemic isochroman compound
(entry 11, see Supplementary data). It should be noted that in some
cases (Table 2, entries 4 and 10) the reactions afforded an insepa-
rable mixture of the expected compounds and the dithioacetal
intermediates, as revealed by TLC and 1H NMR spectroscopy. Con-
sequently, in this case, the resulting isothiochroman (Table 2, entry
4) was isolated as a sulfone after its oxidation by hydrogen perox-
ide in the presence of acetic acid.
Table 2
Synthesis of isothiochroman from phenylethanethiol or phenylethanol
O
XH
R
R1
X
Bi(OTf)3 (0.1 eq)
toluene, 100 ºC
(110 ºC for X=O)
R
R1
X = O, S
Entry
X
R
R1
Reaction time (h)
Yieldsa (%)
1
2
3
4
5
6
7
8
9
S
S
S
S
S
S
S
O
O
O
O
3-NO2–Ph–
2-MeO–Ph–
Ph–
Naphthyl–
3-CHO–Ph–
Ph–
2-HO2C–Ph–
3-NO2–Ph–
4-NO2–Ph–
Ph–
H–
H–
H–
H–
H–
CH3–
H–
H–
H–
H–
H–
2
2.5
2
2
3
88
40
94
68b
Bi(III)
X
53c
X
R
O
H
H
R
15
<25d
2
6
6
6
7
68e
2
80
84
XH
Bi(III)
R
Bi(III)
10
11
Inseparable mixture
2,6-Cl2–Ph–
52f
a
Products characterized by 1H, 13C NMR and MS.20
.
b
O
Yield after two steps (product isolated as sulfone after oxidation with H2O2,
AcOH).
X = O, S
X
H
H
c
Yield for the di-isothiochroman product (2 equiv thiol was added).
d
e
f
Yield in dithioacetal, estimated by 1H NMR.
Yield for the phthalide.
R
Recrystallization in petroleum ether/cyclohexane.
Scheme 1.

C. Lherbet et al. / Tetrahedron Letters 49 (2008) 5449–5451
5451
3. Liu, J.; Birzin, E. T.; Chan, W.; Yang, Y. T.; Pai, L.-Y.; DaSilva, C.; Hayes, E. C.;
Mosley, R. T.; DiNinno, F.; Rohrer, S. P.; Schaeffer, J. M.; Hammond, M. L. Bioorg.
Med. Chem. Lett. 2005, 15, 715.
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6. De Waard, E. R.; Reus, H. R.; Huisman, H. O. Tetrahedron Lett. 1973, 44, 4315.
7. Almena, J.; Foubelo, F.; Yus, M. J. Org. Chem. 1996, 61, 1859–1862.
8. Suzuki, I.; Shigenaga, A.; Manabe, A.; Nemoto, H.; Shibuya, M. Tetrahedron
2003, 59, 5691.
9. Hamura, T.; Hosoya, T.; Yamaguchi, H.; Kuriyama, Y.; Tanabe, M.; Miyamoto,
M.; Yasui, Y.; Matsumoto, T.; Suzuki, K. Helv. Chim. Acta 2002, 85, 3589.
10. Le Roux, C.; Gaspard-Houghmane, H.; Dubas, J.; Jaud, J.; Vignaux, P. J. Org. Chem.
1993, 58, 1835.
Extension of this methodology to the preparation of 2-alkylated
isothiochroman derivatives starting from ketones was then inves-
tigated. Contrary to expectations, in the same experimental condi-
tions no isothiochroman was obtained from acetophenone after
15 h (Table 2, entry 6). In fact, control experiments revealed that
Bi(OTf)3 did not efficiently catalyze the formation of the dithio-
acetal intermediate. It should be noted that neither BiCl3 nor other
bismuth(III) salts were found to catalyze the reaction in our condi-
tions, although these catalysts have proven to be efficient for the
preparation of cyclic dithioacetal such as 1,3-dithiane from both
aliphatic and aromatic aldehydes and ketones.17
When phthaldehydic acid was used as starting aldehyde (Table
2, entry 7), the corresponding thioether was observed as the sole
isolated product in the presence of bismuth triflate. It should be
noted that the same compound was obtained when p-toluenesul-
fonic acid was used as acid catalyst.21
11. Le Roux, C.; Mandrou, S.; Dubac, J. J. Org. Chem. 1996, 61, 3885.
12. Le Boisselier, V.; Coin, C.; Postel, M.; Dunach, E. Tetrahedron Lett. 1995, 51,
4991.
13. Zevaco, T.; Dunach, E.; Postel, M. Tetrahedron Lett. 1993, 34, 2601; Le Boisselier,
V.; Dunach, E.; Postel, M. J. Organomet. Chem. 1994, 482, 119.
14. Garrigues, B.; Gonzaga, F.; Robert, H.; Dubac, J. J. Org. Chem. 1997, 62, 4880.
15. Ollevier, T.; Nadeau, E. J. J. Org. Chem. 2004, 69, 9292; Ollevier, T.; Nadeau, E.
Synlett 2006, 219; Ollevier, T.; Nadeau, E.; Guay-Begin, A.-A. Tetrahedron Lett.
2006, 47, 8351; Ollevier, T.; Nadeau, E.; Eguillon, J.-C. Adv. Synth. Catal. 2006,
348, 2080; Ollevier, T.; Nadeau, E. Org. Biomol. Chem. 2007, 5, 3126; For a
review see: Ollevier, T.; Desroy, V.; Nadeau, E. ARKIVOC 2007, 10.
16. Srivastava, N.; Dasgupta, S. K.; Banik, B. K. Tetrahedron Lett. 2003, 44, 1191.
17. Komatsu, N.; Uda, M.; Suzuki, H. Synlett 1995, 984.
18. General procedure to get isothiochroman derivatives from phenylethanethiol: To a
solution of aldehyde (1 equiv, 0.37 mmol) in toluene (5 mL) were added
phenylethanethiol or phenylethanol (1 equiv) and Bi(OTf)3 (0.1 equiv),
successively. The reaction mixture was warmed up slowly to 100 °C (110 °C
for phenylethanol) and stirred for 2 h. The mixture was cooled, and EtOAc
(5 mL) was added to the mixture. The organic layer was then washed with
water (2 Â 20 mL), dried over MgSO4 and concentrated under reduced
pressure. The desired compound was purified by flash chromatography
S
OH
CHO
Entry 7
O
OH
O
O
O
O
In conclusion, it was demonstrated that iso(thio)chromans can
be efficiently prepared from phenylethanethiol or phenylethanol
and different benzaldehydes in the presence of Bi(OTf)3. Bis-
muth(III) was shown to be essential both in the dithioacetal forma-
tion initial step and in the cyclization to form the isothiochroman
derivative. The procedure was found to be highly efficient, giving
the desired compounds in good to excellent yields. Finally, the
established protocol will be extended to (substituted-phenyl)-
ethanethiol derivatives.
(petroleum ether/EtOAc, 95:5). All compounds reported in Table
2 were
characterized by MS, 1H and 13C NMR.
19. Guiso, M.; Marra, C.; Cavarischia, C. Tetrahedron Lett. 2001, 42, 6531.
20. Characterization of selected products: Entry 1: 1H NMR CDCl3, 300 MHz) d 2.89
(m, 2H); 3.15 (m, 2H); 5.24 (s, 1H); 6.89 (d, J = 7.7 Hz, 1H); 7.16 (m, 2H); 7.25
(m, 1H); 7.46 (t, J = 7.8 Hz, 1H); 7.55 (d, J = 7.8 Hz, 1H); 8.11 (m, 2H); 13C NMR
(CDCl3, 100 MHz) d 24.5; 30.6; 45.1; 122.0; 123.6; 126.4; 127.5; 128.6; 129.1;
130.1; 134.8; 135.1; 136.6; 145.6; 148.2. LRMS: (DCI/NH3, m/z) calcd for
C
15H13NO2S: 271.1, found 289.4 (M+NH4)+. Entry 4: (sulfone) 1H NMR (CDCl3,
300 MHz) d 3.29 (m, 1H); 3.61 (m, 3H); 6.31 (s, 1H); 6.84 (d, J = 7.2 Hz, 1H);
7.16 (d, J = 6.0 Hz, 2H); 7.31 (d, J = 4.2 Hz, 2H); 7.42 (t, J = 7.6 Hz, 1H); 7.57 (m,
2H); 7.90 (t, J = 8.2 Hz, 2H); 8.27 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
d 29.4; 45.2; 64.3; 123.8; 125.0; 126.2; 126.9; 127.4; 128.2; 128.9; 129.3;
129.8; 131.1; 132.7, 132.1; 133.8; 133.9. LRMS: (DCI/NH3, m/z) calcd for
Supplementary data
C
19H16O2S: 308.1, found 326.4 (M+NH4)+. Entry 8: 1H NMR CDCl3, 300 MHz) d
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.07.007.
2.83 (m, 1H); 2.87 (m, 1H); 3.97 (m, 1H); 4.19 (m, 1H); 5.84 (s, 1H); 6.71 (d,
J = 7.6 Hz, 1H); 7.11 (m, 1H); 7.21 (m, 2H); 7.53 (t, J = 7.7 Hz, 1H); 7.68 (d,
J = 7.6 Hz, 1H); 8.2 (m, 1H+1H); 13C NMR (CDCl3, 100 MHz) d 28.6; 64.1; 78.6;
123.1; 123.7; 126.2; 126.5; 127.2; 129.1; 129.4; 133.8; 134.8; 135.8; 144.4;
148.3. LRMS: (DCI/NH3, m/z) calcd for C15H13NO3: 255.1, found 273.4
(M+NH4)+.
References and notes
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21. Tanzawa, T.; Shirai, N.; Sato, Y.; Hatano, K.; Kurono, Y. J. Chem. Soc., Perkin Trans.
1 1995, 22, 2845.